Candidate: As a graduate student and postdoctoral fellow I have completed comprehensive research projects concerning numerous aspects of cancer growth and progression to metastasis. I am currently funded by a postdoctoral fellowship from the American Cancer Society. My productivity rate has been very strong for the last six years resulting in consistent publication of high impact manuscripts. I currently hold the position of Senior Research Associate, the highest postdoctoral training rank at Case Western Reserve University. Subsequent to receipt and execution of the mentored phase of this application my ultimate goal is run a productive and dynamic independent research program at a leading university or research institute. Environment: The research and core facilities within the Case Comprehensive Cancer Center are second to none. Within this environment I will be able to seamlessly transition between basic, pre-clinical and clinical research. Within the Schiemann laboratory in particular I have been and will continue to receive extraordinary training in research technique, grant and manuscript preparation, presentation skills, and research management. Furthermore, through the process of preparing this application I have tapped into the significant intellectual resources within the Case Comprehensive Cancer Center. I have sought out advice and guidance from numerous high level investigators whose input has aided me in constructing a focused and clinically relevant proposal. This unique training will set me apart as I transition into an independent investigator. Research: The five-year survival rate of breast cancer drops precipitously when diagnosed as late stage metastatic disease. Indeed, current therapies are ineffective at reducing the growth of metastatic breast cancer suggesting that there is a fundamental change in the molecular pathways that drive metastatic outgrowth as opposed to primary tumor growth. By definition triple negative breast cancers (TNBC) lack the required targets of hormonal (estrogen and progesterone receptors) and Her2-targeted therapies. In the context of TNBC, enhanced expression of EGFR within the primary tumor is strongly linked to decreased disease prognosis, suggesting EGFR as an effective target in treating TNBC. However, EGFR-targeted chemotherapies do not offer clinical benefit to TNBC patients. This disconnect between the diagnostic value of EGFR and the clinical failure of EGFRi therapies strongly suggests that TNBCs acquire alternate growth promoting signaling pathways during late-stage tumor recurrence and metastasis. Concomitant with disease recurrence and metastasis is the acquisition of epithelial-mesenchymal transition (EMT). Despite recent advances in elucidating the molecular players involved in the conversion of cells from an epithelial to mesenchymal state, little is known about the specific changes in molecular signaling pathways that result as a consequence of EMT. Ligand stimulation of EGFR leads to the robust activation of both mitogen activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (Stat3) pathways, but how these signaling pathways are affected by EMT remains unexplored. In the first Aim we propose that aberrant initiation of EMT facilitates mammary tumor cell dissemination from the primary lesion by causing a fundamental switch in EGFR function from proliferation to invasion. We further propose that this switch in function requires the loss of EGFR-mediated Stat3 activation. To address this hypothesis we will use genetic and pharmacological approaches to modulate Stat3 expression and/or activity, and assess the impact of these Stat3 modifications on the ability of EMT to enhance breast cancer growth and metastasis. Furthermore, we will employ a novel dual- substrate bioluminescence technique to track real-time in vivo Stat3 activity as orthotopic mammary tumors grow and metastasize. As a consequence of the EMT-mediated switch in EGFR function, following systemic dissemination, other growth factor signaling pathways must be upregulated to facilitate metastatic outgrowth. Based on our preliminary data, in Aim 2 we will address the hypothesis that upregulation of fibroblast growth factor receptor (FGFR) is capable of replacing EGFR as the dominant mitogenic signaling module during metastatic outgrowth of TNBC. This switch in growth factor dependence from EGF to FGF presents a plausible mechanism by which recurrent and metastatic TNBC is unaffected EGFR-targeted therapies. Therefore, we will use genetic and pharmacological approaches to target FGFR and effectively inhibit recurrent and metastatic TNBC lesions. Finally, in Aim3 we will use a novel insertional mutagenesis technique to screen for potential mediators of EGFRi-insensitivity. In addition we will functionally characterize the diagnostic potential of FGFR and Tensin1 two members of our recently established 12-gene signature of EGFRi-insensitivity. We will utilize human breast cancer specimens of known diagnosis, treatment, and outcome to establish a diagnostic platform that would identify TNBC patients most likely to respond to FGFRi therapy. Overall, the proposed studies will address current gaps in knowledge concerning the molecular mechanisms by which EMT evolves TNBC growth promoting signaling from EGFR to FGFR, leading to the failure of EGFR-targeting agents in treating late-stage TNBC. More importantly, our studies will establish a diagnostic platform and therapeutic protocol for the inhibition of FGFR as an effective treatment option for TNBC patients undergoing metastatic tumor recurrence.

Public Health Relevance

Currently, the 5-year survival rate of patients diagnosed with metastatic breast cancer is only 23% and triple negative breast cancers (TNBC) lack an effective molecular target. This proposal will use cutting edge technologies to visualize and target Stat3 and FGFR signaling as key molecular events that drive the outgrowth of TNBCs at a metastatic site. Therefore, the impact of this proposal will be to define novel drugable target capable of improving the prognosis of patients diagnosed with advanced TNBC. The written critiques and criteria scores of individual reviewers are provided in essentially unedited form in the Critique section below. Please note that these critiques and criteria scores were prepared prior to the meeting and may not have been revised subsequent to any discussions at the review meeting. The Resume and Summary of Discussion section above summarizes the final opinions of the committee.